Her-2/neu (referred to henceforth as “Her-2”) is a 185 kDa glycoprotein that is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinases, and is overexpressed in 25 to 40% of all breast cancers and in many cancers of the bone (osteosarcoma—OSA), ovaries, lung, pancreas, brain, and gastrointestinal tract. Patients with cancers that overexpress Her-2 exhibit tolerance even with detectable humoral, CD8+ T cell, and CD4+ T cell responses directed against Her-2.
Large breed dogs spontaneously develop OSA that recapitulates many aspects of human pediatric OSA including histologic heterogeneity, aggressive local disease and early metastases. At diagnosis, 95% of dogs have micrometastatic disease and despite amputation and chemotherapy, the median survival time is 10 months with most dogs euthanized due to progressive metastatic disease. The overall survival of human patients with metastatic osteosarcoma ranges from 10-50%, depending on the location and the number of metastatic foci.
Radiation therapy (RT), which is used to destroy tumor cells or to alter tumor/stroma architecture, is an integral part of treatment of many types of cancer. However, because OSA is radioresistant to standard dose of radiotherapy, it is not used for treating OSA.
Recently there has been evidence that RT may synergize with targeted immune therapy. For example, RT induces immunogenic cell death wherein tumor cells die slowly over time from apoptosis, necrosis and/or mitotic catastrophe, leading to the clearance of the dying cells by the immune system. This in turn serves as a potential source of tumor antigens for immune therapy. RT also modulates tumor cell surface expression of cell death receptors, tumor-associated antigens and adhesion molecules, which render the tumor cells more susceptible to immune-mediated killing.
The present invention meets the needs of subjects suffering from OSA with surprising findings that radiation therapy when combined with a recombinant Listeria-Her-2/neu vaccine (ADXS31-164) that was generated using the LmddA vaccine vector which has a well-defined attenuation mechanism and is devoid of antibiotic selection markers is particularly effective against osteosarcoma and pulmonary metastasis.